U.S. patent application number 16/484706 was filed with the patent office on 2021-05-13 for method of use for therapeutic bone agents.
This patent application is currently assigned to IGL Pharma, Inc.. The applicant listed for this patent is IGL Pharma, Inc.. Invention is credited to R. Keith Frank, Jaime Simon.
Application Number | 20210138095 16/484706 |
Document ID | / |
Family ID | 1000005385838 |
Filed Date | 2021-05-13 |
United States Patent
Application |
20210138095 |
Kind Code |
A1 |
Simon; Jaime ; et
al. |
May 13, 2021 |
METHOD OF USE FOR THERAPEUTIC BONE AGENTS
Abstract
This invention relates to radioactive, bone-seeking,
pharmaceutical compositions that are administered multiple times to
a patient, have a lower impurity profile, a longer shelf life, and
are less expensive to prepare.
Inventors: |
Simon; Jaime; (Angleton,
TX) ; Frank; R. Keith; (Lake Jackson, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
IGL Pharma, Inc. |
Angleton |
TX |
US |
|
|
Assignee: |
IGL Pharma, Inc.
Angleton
TX
|
Family ID: |
1000005385838 |
Appl. No.: |
16/484706 |
Filed: |
February 6, 2018 |
PCT Filed: |
February 6, 2018 |
PCT NO: |
PCT/US2018/017082 |
371 Date: |
August 8, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62456191 |
Feb 8, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 51/0478 20130101; A61K 51/0482 20130101 |
International
Class: |
A61K 51/04 20060101
A61K051/04; A61P 35/00 20060101 A61P035/00 |
Claims
1. A method for the treatment of a patient having bone pain, on or
more calcific tumors, or in need of a bone marrow suppressing
procedure, comprising administering to said patient a
pharmaceutically-acceptable formulation of a chelate composition
comprising a Clinically Relevant Dosage of the composition that is
therapeutically effective as Multiple Doses without a quantifiable
accumulation of long-lived isotopes in the patient, said
composition possessing an extended Expiration Date of the Sm-153
used to prepare the composition of greater than or equal to about 5
days based on Eu-154 present in the formulation being less than
0.093 .mu.Ci Eu-154/mCi Sm-153 and said chelate comprises LSA
Sm-153 and DOTMP or a physiologically-acceptable salt thereof.
2. The method of claim 1 wherein the amount of Sm-153 is about 0.3
to 1.5 mCi/kg or more.
3. The method of claim 2 wherein the amount of Sm-153 is about 0.5
mCi/kg.
4. The method of claim 1 wherein the Expiration Date of the Sm-153
used to prepare the chelate composition is about 10 days or
more.
5. The method of claim 1 wherein the Multiple Doses are at least 2
doses for a patient that is administered at 3 month intervals.
6. The method of claim 1 wherein the Multiple Doses are at least 10
doses for a patient administered over 3 month intervals for the
first 5 doses, then over 6 month intervals for the last 5
doses.
7. The method of claim 1 wherein the composition contains equal to
or than 0.093 .mu.Ci of Eu-154 per mCi of Sm-153 at expiry.
8. The method of claim 1 wherein the Clinically Relevant Dosage is
about 0.5 mCi per kg body weight or about 30 mCi for a 70 kg
patient.
9. The method of claim 1 wherein the Clinically Relevant Dosage is
about 1.0 mCi per kg body weight or about 70 mCi for a 70 kg
patient.
10. The method of claim 1 wherein the pharmaceutically-acceptable
formulation comprises one or more of a suitable solvent,
preservatives, diluents, excipients and buffers.
11. The method of claim 9 wherein the formulation solvent is water,
aqueous alcohols or glycols.
12. A chelate composition comprising a Clinically Relevant Dosage
of the composition that is therapeutically effective and
pharmaceutically-acceptable, said composition possessing an
extended Expiration Date of the Sm-153 used to prepare the
composition that is greater than or equal to about 5 days and said
chelate comprises Sm-153 and DOTMP or a physiologically-acceptable
salt thereof.
13. The chelate composition of claim 12 wherein said composition is
prepared from Sm-153 at end of irradiation has a specific activity
is less than 3 Ci/mg.
14. The chelate composition of claim 12 wherein said composition is
prepared from Sm-153 which had a Eu-154 concentration less than 10
.mu.Ci Eu-154 per Ci Sm-153 at end of irradiation.
15. The chelate of claim 12 wherein said composition is prepared
from Sm-153 that was produced in a nuclear reactor at a flux less
than 1E14 neutrons/cm.sup.2-sec and said chelate comprises Sm-153
and DOTMP or a physiologically-acceptable salt thereof wherein the
Sm-153 dosage is at least 30 mCi.
16. The method of claim 5 wherein the Multiple Doses are at least 5
to 100 doses for a patient that is administered at 3 month
intervals.
Description
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] The invention relates a method of use of bone-seeking
radioactive metal-chelant formulations that are suitable for
administration to a patient having: bone pain; one or more calcific
tumors; or in need of a bone marrow suppression procedure, where
that method of treating a patient involves multiple treatments with
low specific activity (LSA) Sm-153
1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid
(DOTMP).
Description of Related Art
[0002] Bone cancer can be primary or metastatic. Primary cancer
occurs when the bone cells themselves are cancerous, and although
this is a relatively rare disease, it is a very aggressive one,
primarily effecting younger patients. Present treatment options
include chemotherapy and external beam therapy, and in many
patients an affected limb is amputated. Metastatic bone cancer
occurs when cancer cells from soft tissue cancers grow on the bone.
Cancers arising from prostate, breast and lung have a significant
propensity to metastasize to bone in this way. Metastatic bone
cancer can be associated with significant pain, decreasing the
patient's ability to function. Controlling the pain is accomplished
by increasing amounts of narcotics, significantly decreasing
quality of life for the patient.
[0003] Radiopharmaceuticals, radioactive drugs, have been used as
treatments for bone cancers. Cancer cells growing in the bone cause
higher turnover of the bone in close proximity to them. The
strategy for these drugs is to target this fast-growing bone. Note
that these bone-seeking radiopharmaceuticals do not target cancer
cells themselves but the nearby bone tissue.
[0004] Two classes of these radiopharmaceutical agents have been
used for this purpose. The first class involves a radioactive metal
salt. Examples of such agents are Sr-89 and Ra-223, both formulated
as the chloride salt. These metals mimic calcium and thus
concentrate in bone. Strontium-89 has a long half-life (50.57 days)
and a high beta energy (maximum beta energy is 1.463 MeV). These
two characteristics in conjunction with the lack of an imageable
gamma photon have significantly reduced the use of this Sr-89
agent. Radium-223 is an alpha-emitting radioisotope that follows a
decay chain producing a variety of daughter isotopes. The range of
alpha particles is very short (about 0.1 mm) compared to that of
beta particles (about 0.3 mm) and may limit the utility of Ra-223
to effectively treat bone cancer.
[0005] A second class of bone-seeking radiopharmaceuticals is
comprised of phosphonic acid chelates, such as
Sm-153-ethylenediaminetetramethylenephosphonic acid in which the
radioactive Sm is chelated to the phosphonic acid,
ethylenediaminetetramethylenephosphonic acid (EDTMP). One such
example is Quadramet.RTM. (trademark of EUSA PHARMA (USA), INC)
that is a commercially available chelate formed between Sm-153 and
EDTMP that is currently indicated for the pain associated with bone
metastases (U.S. Pat. No. 4,898,724).
[0006] U.S. Pat. No. 5,059,412 teaches the use of Sm-153, Gd-159,
Ho-166, Lu-177 and Yb-175 chelates with chelants derived from the
1,4,7,10-tetraazacyclododecane moiety including
1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid
(DOTMP), while U.S. Pat. No. 5,064,633 teaches the above metals
plus Y-90.
[0007] A therapeutically effective biodistribution (fate of the
activity after administration) for a therapeutic bone agent
includes high bone uptake, low soft tissue uptake, rapid clearance
of the activity not associated with bone, and high lesion-to-normal
bone ratio. Compositions that do not have these characteristics are
detrimental to the patient. For example, high soft tissue uptake
would result in the patient receiving a high radiation dose to the
liver, bone marrow or other soft tissue leading to undesirable side
effects.
[0008] The phosphonic acid ligand keeps the Sm soluble and delivers
it to bone. In this case the decay of Sm-153 gives off beta
particles, which are useful for treating the tumor, and gamma
photons which are useful for determining the fate of the isotope
via gamma camera imaging. Also the half-life of Sm-153 is about 46
hours. Although these conditions seem ideal, the EDTMP/Sm complex
is relatively labile and therefore there is a need to use a large
excess of chelating agent relative to Sm (about 300:1 ligand to
metal ratio). Because of this excess ratio, it is also necessary to
use high specific activity (HSA) Sm-153. The preparation of HSA
samarium-153 results in a significant amount of long-lived
radionuclidic impurities (see FIG. 2). These long-lived isotopes
make waste disposal more difficult and these isotopes accumulate in
a patient's bone when they undergo multiple treatments. In a study
by Sinzinger et al., QJ NUCL MED MOL IMAGING 2001; 55:420-30), they
discuss the long-lived impurities such as Eu-154, present in Sm-153
EDTMP when multiple doses are administered to patients using
high-resolution gamma spectroscopy as whole body counters (see FIG.
3). Their results showed that the undesirable doses due to the Eu
isotopes increases with every treatment. The effect of the
long-lived isotopes in patients is unknown, therefore this
accumulation is undesirable.
[0009] All currently available radiopharmaceuticals for this
purpose have drawbacks, and there is a need for an improved
radiopharmaceutical agent to treat bone cancer.
[0010] Toward that purpose, the inventions discussed in WO
2015/054173 and WO 2016/191413 have been made by the present
applicant and which are hereby incorporated by reference. WO
2015/054173 discloses a method for treating patients with LSA
Sm-153 DOTMP and a 2 vial kit. WO 2016/191413 discloses an improved
kit formulation having 3 vials that enables LSA Sm-153 DOTMP to be
made more accurately and easily at a radiopharmacy.
[0011] Radionuclides such as Sm-153 are prepared in a nuclear
reactor by bombarding purified targets of the element containing
one less neutron and in the process generate radionuclidic
impurities. For example, to produce Sm-153 the target that is
irradiated is Sm-152 and Eu-154 is an unwanted impurity that is
also formed.
[0012] The impurities can be detrimental to institutions from both
a patient and a waste disposal standpoint. For example, too much
Eu-154 administered to a patient would result in the isotope giving
an undesirable dose to a patient for a long period of time,
especially when multiple injections for treatment are done. In
addition, the dose that is excreted in the urine by the patient
containing Eu-154 is a concern and institutions may be forced to
collect the radioactive urine. Disposal of the product vials
containing residual activity can be a problem. These vials and
syringes are typically allowed to decay for 10 half-lives prior to
disposal. This is a reasonable amount of time for Sm-153 (about 20
days) but not for Eu-154 (about 86 years). Processes must be
implemented in order to deal with waste disposal of vials and
syringes that are used. This makes the use of these types of
radiopharmaceuticals more complex and institutions may chose not to
use the drugs.
[0013] In addition, these long-lived impurities cause issues with
the radioactive licensing process for the facility. Typically
institutions are only allowed small amounts of long-lived
radionuclides (having half-lives greater than 120 days) before they
are required to have financial assurance. Financial assurance can
be very expensive, especially for institutions that only handle
short-lived isotopes.
[0014] The specifications for Quadramet.RTM. (Sm-153 EDTMP) call
for the product to contain less than 0.093 microcuries of Eu-154
per millicurie of Sm-153 at expiry
(http://health.phys.iit.edu/extended_archive/0001/msg00922.html,
http://acnp-cal.org/SM153INS.html) or 4 days from the manufacture
date (http://www.ibamolecular.eu/products/quadramet). This
restriction limits the expiration time of the drug. Since Sm-153
decays faster than Eu-154, the longer the Sm-153 solution decays,
the higher the amount of Eu-154 is in the sample relative to
Sm-153. Thus expiration of not only formulated Quadramet.RTM. (e.g.
Ca-EDTMP+Sm-153) but also the Sm-153 used to produce Quadramet.RTM.
is limited by the amount of Eu-154 in the sample.
[0015] In nuclear reactors such as the one at the University of
Missouri in Columbia Mo., the Sm-152 samples are irradiated for one
week in the "flux trap" (see FIG. 1) in order to produce the high
specific activity (HSA) Sm-153 required for the production of
Quadramet.RTM.. The flux trap is only accessed once a week and
therefore high specific activity Sm-153 can only be produced on a
weekly basis. Because of the growing amount of Eu-154 compared to
Sm-153 over time, the Sm-153 isotope can only be used for a short
period of time. Thus the drug is not available to treat patients on
some days of the week. The flux trap portion of the reactor is also
the most expensive to access (requiring reactor shut-down) thus
increasing the production cost of the HSA Sm-153 isotope.
[0016] Clearly, there is a need for a product with a longer shelf
life and a better impurity profile for use for multiple treatments
to patients.
BRIEF SUMMARY OF THE INVENTION
[0017] The present invention provides a method for the treatment of
a patient having bone pain, one or more calcific tumors, or in need
of a bone marrow suppressing procedure, comprising administering to
said patient multiple doses of a pharmaceutically-acceptable
formulation of a chelate composition comprising a Clinically
Relevant Dosage of the composition that is therapeutically
effective in multiple injections without the accumulation of
long-lived isotopes in the patient, wherein the Sm-153 used to
prepare said composition possesses an extended Expiration Date of
greater than or equal to about 5 days based on the Eu-154 present
in the formulation being less than 0.093 .mu.Ci Eu-154 per mCi
Sm-153. The chelate composition comprises LSA Sm-153 and DOTMP or a
physiologically-acceptable salt thereof wherein the Sm-153 dosage
is at least about 30 mCi per dose.
[0018] Each treatment results in lower toxicity to the bone marrow
and a less accumulation of long-lived radionuclidic isotopes in the
patient when compared with use of HSA Sm-153 chelates. The present
invention involves the treatment of such bone cancer using low
specific activity (LSA) Sm-153 chelated to a macrocyclic chelating
agent, DOTMP. LSA Sm-153-DOTMP is easier and more readily available
to prepare and incurs significantly lower cost in comparison to
high specific activity (HSA) Sm-153. This was discussed in WO
2015/054173 which is hereby incorporated by reference. The present
invention provides the use of this LSA Sm-153 DOTMP as a multiple
injection treatment to the patient or patient without the undesired
accumulation of long-lived isotopes such as Eu-154.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1: Schematic of the available irradiation positions at
the University of Missouri Research Reactor (MURR). High specific
activity (HSA) Sm-153 is prepared in the flux trap which requires
reactor shut down and is expensive. Low specific activity (LSA)
Sm-153 is prepared in the reflector, which is much easier to access
and can be done frequently. Provided courtesy of MURR.
[0020] FIG. 2: High resolution gamma spectra of HSA Sm-153 showing
long lived radioactive impurities. H. Fisher, et al.,
"Radionuclidic purity aspects of Sm-153 for radionuclide therapy,"
Proceedings of the International Congress of the International
Radiation Protection Agency, May, 2004.
[0021] FIG. 3: Radioactive Eu-impurities detected in bone after 1,
7 and 10 treatments with 153Sm-EDTMP. H. Fisher, et al.,
"Radionuclidic purity aspects of Sm-153 for radionuclide therapy,"
Proceedings of the International Congress of the International
Radiation Protection Agency, May, 2004.
DETAILED DESCRIPTION OF THE INVENTION
[0022] It is understood that the terminology used herein is for the
purpose of describing particular embodiments only and is not
intended to be limiting. As used in this specification, the
singular forms "a", "an", and "the" include plural referents unless
the content clearly indicates otherwise. The following terms in the
Glossary as used in this application are to be defined as stated
below and for these terms, the singular includes the plural.
[0023] Various headings are present to aid the reader, but are not
the exclusive location of all aspects of that referenced subject
matter and are not to be construed as limiting the location of such
discussion.
[0024] Also, certain US patents and PCT published applications have
been incorporated by reference. However, the text of such patents
is only incorporated by reference to the extent that no conflict
exists between such text and other statements set forth herein. In
the event of such conflict, then any such conflicting text in such
incorporated by reference US patent or PCT application is
specifically not so incorporated in this patent.
Glossary
[0025] % means weight percent, unless stated otherwise [0026]
Patient means any warm-blooded animal or mammal or human; any of
which can be treated as described for this invention [0027]
Clinically Relevant Dosage means enough activity to cause either
pain palliation or reduction of tumor burden. This dosage is about
0.5 mCi per kg body weight or about 30 mCi per dose for a 70 kg
patient; more preferred 1.0 mCi per kg body weight or about 70 mCi
per dose for a 70 kg patient. Higher amounts of radioactivity may
be administered to the patients or for treating tumor regression or
bone marrow ablation in patients. [0028] DOTMP means
1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid [0029]
EDTMP means ethylenediaminetetramethylenephosphonic acid Expiration
Date means the number of days after production when Sm-153 contains
equal to or greater than 0.093 .mu.Ci of Eu-154 per mCi of Sm-153.
[0030] FDA means US Food and Drug Administration [0031] HSA means
high specific activity that for Sm-153 is defined as greater than
about 4 Ci/mg that is prepared by irradiating at a neutron flux
greater than 1E14 neutrons/m.sup.2 sec for greater than 120 hours
[0032] LSA means low specific activity that for Sm-153 is defined
as less than about 4 Ci/mg and is prepared by irradiating at a
neutron flux less than about 1E14 neutrons/m.sup.2 sec for less
than 120 hours [0033] Ci means curies [0034] .mu.Ci means
microcuries [0035] mCi means millicuries [0036] Multiple Doses
means treatment of the patient with two or more doses of a
Clinically Relevant Dosage of Sm-153 DOTMP, the number of doses can
be from 2 to an indefinite number of doses, such as 5 to 100 doses
to a patient; these doses are generally spaced over time such as at
every 3 months, 6 months or 12 months intervals
DISCUSSION
[0037] The specific activity of an isotope is sometimes a source of
confusion because it is expressed in many ways (see Practical
Aspects of labeling DTPA and DOTA peptides with Y-90, In-111,
Lu-177 and Ga-68 for Peptide-Receptor Scintigraphy and
peptide-Receptor Radionuclide Therapy in preclinical and Clinical
Applications at
http://pharmacyce.unm.edu/program_information/freelessonfiles/Voll6Lesson-
5.pdf).
[0038] For this invention, the specific activity of an isotope is
defined as the radioactivity (mCi or Bq) of the isotope in question
divided by the mass of all of the isotopes (stable and radioactive)
of the element. For example for reactor produced Sm-153 where the
starting material is Sm-152 that is converted to Sm-153, the
specific activity of Sm-153 is the amount of radioactivity of
Sm-153 in the sample divided by the total mass of any Sm element in
the sample (e.g. activity Sm-153/sum of masses of Sm-152 and
Sm-153). The units of the number are typically in Curies per gram
(Ci/g) or Curies per mole (Ci/mole). In some cases the percent of
the isotope that is radioactive is reported. For example in reactor
produced Sm-153, only about 2% of the Sm is Sm-153 and about 98% is
non-radioactive Sm-152.
[0039] Traditionally, nuclear medicine scientists strive to
increase the specific activity of the isotopes of interest. For
example, two government grants for providing high specific activity
isotopes have been recently awarded (High Specific Activity Sm-153
by Post Irradiation Isotope Separation, DOE SBIR grant Solicitation
Number DE-FOA-0000676, and Production of Commercial High Specific
Activity Sn-117m Radiochemical and Chelates, DOE grant Solicitation
Number DE-FOA-000782). The use of high specific activity (HAS)
isotopes allows for less mass of the isotope needed to achieve the
same amount of radioactivity. This leads to lower amounts of
chelating agents and/or proteins needed in the radioactive drug. In
addition, in many cases such as with labeled antibodies and
proteins, the receptors on cells (such as cancer cells) that the
drugs target are limited. If the specific activity of the isotope
is low (e.g. 2% of the atoms are radioactive), then the amount of
active drug that reaches the target is relatively small. However,
if the specific activity is high (a larger percentage of the atoms
are radioactive), then the amount of effective drug that reaches
the target is much higher, which explains why so much effort is put
forth in radioisotope production to achieve higher and higher
specific activity.
[0040] Contrary to this conventional wisdom where higher specific
activity isotopes are sought-after as desirable, this invention
utilizes Sm-153 produced in a lower flux portion of the nuclear
reactor (reflector) for a shorter period of time (see FIG. 1),
resulting in a lower specific activity (LSA) isotope with a
significant cost reduction and lower impurity profile. When
combined with DOTMP a product can be produced which comprises a
Clinically Relevant Dosage of Sm-153-DOTMP with a reduced
radionuclidic impurity profile, a longer shelf life, a lower cost
to manufacture, and can be made available to patients on a more
frequent basis. Since the toxicity due to accumulated long-lived
isotopes in multiple dosing regimens (see FIG. 2) is unknown, it is
prudent to reduce these long-lived isotopes in the formulation by
utilizing LSA Sm-153. This in turn allows multiple doses of the LSA
Sm-153 chelated to DOTMP to be administered. For example more than
two doses to the patient up to 100 doses or more.
[0041] The present invention provides a method for the treatment of
a patient having bone pain, one or more calcific tumors, or in need
of a bone marrow suppressing procedure, comprising administering to
said patient a pharmaceutically-acceptable formulation of a chelate
composition comprising a Clinically Relevant Dosage of the
composition that is therapeutically effective as Multiple Doses
without a quantifiable accumulation of long-lived isotopes in the
patient, said composition possessing an extended Expiration Date of
the Sm-153 used to prepare the composition of greater than or equal
to about 5 days based on Eu-154 present in the formulation being
less than 0.093 .mu.Ci Eu-154/mCi Sm-153 and said chelate comprises
LSA Sm-153 and DOTMP or a physiologically-acceptable salt thereof.
The Clinically Relevant Dosage is about 0.3 to about 1.5 mCi/kg of
body weight, preferred is about 0.5 mCi per kg body weight or about
30 mCi per dose for a 70 kg patient; more preferred 1.0 mCi per kg
body weight or about 70 mCi per dose for a 70 kg patient. The
Expiration Date, meaning the number of days after production when
Sm-153 contains equal to or greater than 0.093 .mu.Ci of Eu-154 per
mCi of Sm-153, is 5 days, 10 days or more at expiry. Multiple Doses
are at least 5 doses for a patient that is administered at 3 month
intervals; or 10 doses for a patient that is administered at 6
month intervals for the last 5 doses.
[0042] This invention provides a better radiopharmaceutical for the
treatment of bone cancer for the following reasons. The
radiopharmaceutical consists of LSA Sm-153 combined with the
chelating agent, DOTMP. Unlike the chelate formed between Sm and
EDTMP, a commercial product for comparison, the present Sm-DOTMP
complex is not labile and does not easily dissociate. For that
reason, it is possible to prepare a stable complex using a much
smaller ratio of DOTMP to Sm-153 (about 1:1 ligand to metal ratio),
compared to Sm-EDTMP (about 300:1 ligand to metal ratio).
Additionally, this stability allows for the possibility of using
LSA Sm-153 which is more readily available, less expensive, and has
significantly fewer long-lived radionuclidic impurities compared to
HSA Sm-153 (see FIG. 2). In addition, the bone marrow toxicity
associated with a dose of Sm-153-DOTMP is less than that for an
equivalent dose of Sm-153-EDTMP. While not wishing to be bound by
theory, it is believed that the reason for this lessened toxicity
is that the Sm-DOTMP chelate is more stable thereby allowing less
free metal to be released in the formulation and that the chelate
may also have less free metal available as it is diluted in the
bloodstream of a patient. Small amounts of free metal can enter the
bloodstream and precipitate as particles that can be taken up by
bone marrow. Small amounts of radioactive Sm-153 directly deposited
in the marrow in this way may be responsible for additional bone
marrow toxicity. This stability is important when multiple doses
are desired for treatment.
[0043] The formulations of the present invention may be in a kit
form such that the two components (chelant and isotope) are mixed
at the appropriate time prior to use or in a three component kit as
described in WO 2016/191413. Whether pre-mixed as the drug or as a
kit where the drug is made on site, the formulations require a
pharmaceutically-acceptable carrier. Such carriers comprise any
suitable pharmaceutically-acceptable carrier such as one or more of
a suitable solvent, preservatives, diluents, excipients and
buffers. Useful solvents include, for example, water, aqueous
alcohols and glycols. The formulation is administered to the
patient by injection intramuscularly or intravenously, or near the
tumor or upstream of the blood supply to the tumor.
[0044] The present chelate composition comprises a Clinically
Relevant Dosage of the composition that is therapeutically
effective and pharmaceutically-acceptable, said composition
possessing an extended Expiration Date of the Sm-153 used to
prepare the composition that is greater than or equal to about 5
days and said chelate comprises Sm-153 and DOTMP or a
physiologically-acceptable salt thereof. This composition is
prepared from Sm-153 that at end of irradiation has a specific
activity is less than 3 Ci/mg and a Eu-154 concentration less than
10 .mu.Ci Eu-154 per Ci Sm-153 at end of irradiation. This
composition is prepared from Sm-153 that was produced in a nuclear
reactor at a flux less than 1E14 neutrons/cm.sup.2-sec and said
chelate comprises Sm-153 and DOTMP or a physiologically-acceptable
salt thereof wherein the Sm-153 dosage is at least 30 mCi.
[0045] The invention will be further clarified by a consideration
of the following examples, which are intended to be purely
exemplary of the invention.
[0046] Materials and Equipment:
[0047] The radioactive isotopes were purchased from The University
of Missouri Research Reactor.
[0048] Chelants were purchased from commercial sources or were
prepared as described in U.S. Pat. No. 5,059,412.
[0049] General Procedure
[0050] In the following examples, the lettered examples are
comparative, and the numbered examples are this invention.
Example A: Comparative--Production of Sm-153 in MURR (University of
Missouri Research Reactor) Reactor Flux Trap
[0051] One mg of Sm-152, as Samarium oxide, was sealed in a quartz
vial and irradiated for approximately 150 hours in the flux trap at
MURR (HSA). The ratio of Eu-154 to Sm-153 at end of irradiation was
approximately 18 .mu.Ci Eu-154 per Ci of Sm-153.
Example B: Comparative--Treatment of Patients with Flux
Trap-Irradiated Sm-153 (HSA)
[0052] The Sm-153 prepared as in Example A was used to prepare
doses of Sm-153-EDTMP. These doses were used to treat patients
suffering from bone cancer. Patients were repeatedly treated (10
times) with 30 mCi of Sm-153-EDTMP as prepared in this example. The
first 5 doses were given at 3 month intervals, and the second five
doses given at 6 month intervals. After the decay of Sm-153, a NaI
crystal was used to detect the amount of residual activity in the
patients. After receiving 7 doses, there were significant amounts
of activity detected in patients, which increased with each dose
given thereafter. The activity was due to long-lived radionuclidic
impurities created during the target irradiation process.
Example C: Comparative--Vienna Protocol by Dr. Helmut Sinzinger et
al., QJ NCUL MED MOL IMAGING 2001; 55:420-30)
[0053] About 550 patients were repeatedly dosed with 30 mCi of
Sm-153-EDTMP to treat prostate and breast bone metastases for pain
palliation. These multiple does were as follows: 5 at 3 month
intervals; 5 at 6 month intervals; 5 at 9 month intervals; and
several indefinitely at 12 month intervals.
[0054] The results showed lesion regression and improved survival.
However, the long-lived impurities in HSA Sm-153-EDTMP were
apparent as shown in FIG. 2. The build-up of these long-lived
isotopes is seen in FIG. 3.
Example 1: Production of Sm-153 in MURR Reflector (LSA)
[0055] One mg of Sm-152, as Samarium oxide, was sealed in a quartz
vial and irradiated for 2 days in the reactor reflector at MURR.
The ratio of Eu-154 to Sm-153 at end of irradiation was
approximately 0.5 .mu.Ci of Eu-154 per Ci of Sm-153.
Example 2: Treatment of Dogs with LSA Sm-153-DOTMP
[0056] Seven dogs with osteosarcoma were treated with the
Sm-153-DOTMP made from LSA Sm-153 of Example 1 at 1 mCi/kg. There
was uptake in the tumor for all dogs. The dogs displayed about one
half of the myelosuppression of similar dogs treated with 1 mCi/kg
of HSA Sm-153-EDTMP as evidenced from the nadir in platelets and
neutrophils.
Example 3: MTD of LSA Sm-153-DOTMP
[0057] An ascending dose trial of 13 dogs starting at 1.5 mCi/mg
was done which showed uptake in tumor for all seven dogs tested.
The maximum tolerated dose is 1.75-2.0 mCi/kg; whereas for
Sm-153-EDTMP the maximum tolerated dose was 1.0 mCi/kg. Stable or
improved indices were experienced by 7 of 12 dogs.
Example 4: Treatment of Patients with Reflector-Irradiated Sm-153
(LSA)
[0058] The Sm-153 prepared as in Example 1 will be used to prepare
doses of Sm-153-DOTMP. These doses will be used to treat patients
suffering from bone cancer. Patients are to be repeatedly treated
(10 times) with 30 mCi of Sm-153-DOTMP as prepared in this example.
The first 5 doses will be given at 3 month intervals and the second
five doses given at 6 month intervals. After the decay of Sm-153, a
NaI crystal will be used to detect the amount of activity in the
patients. Even after 10 doses there should be no detectable amounts
of activity from long-lived radionuclidic impurities in the
treatment found in the patients.
[0059] Although the invention has been described with reference to
its preferred embodiments, those of ordinary skill in the art may,
upon reading and understanding this disclosure, appreciate changes
and modifications which may be made which do not depart from the
scope and spirit of the invention as described above or claimed
hereafter. Accordingly, this description is to be construed as
illustrative only and is for the purpose of teaching those skilled
in the art the general manner of carrying out the invention.
* * * * *
References